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ANNUAL
REVIEWS

Quick links to online content

Further

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Ann. Rev. Physiol. 1987. 49:1-15

Copyright 1987 by Annual Reviews Inc. All rights reserved

A SILVER SPOON
J. R. Pappenheimer
Department of Physiology and Biophysics, Harvard Medical School,
Street, Boston, Massachusetts

25

Shattuck

02115

An invitation to write the prefatory chapter for the Annual Review of

Physiology provokes mixed feelings. There is no question as to the honor it

confers; a glance at the list of previous invitees attests to that. On the other
hand, it signals the unwanted passage of time, and it implies that the invitee,
a fter

50 years of physiology, should have profound and useful things to say

about the past and future. Alas, I must confess at the outset that the pearls of
wisdom within my shelLhave been slow to mature, and they are still too small
to spread before the sophisticated readers of

this Annual Reviews volume. I

can only use them as decorations for a personal narrative.

PRELUDE
I was born in

1915 in New York City. My father, Alwin M. Pappenheimer,

Sr., was Professor of Pathology at Columbia University and one of the

leading experimental pathologists of his day. He came from a well-to-do

family and had every opportunity to make use of his natural talents for both
science and the art of living. The summers of his youth were spent travelling

fluently. He made many

paintings, and he played the violin and viola well

in Europe, and he spoke French and German

drawings, etchings, and

enough to participate in most of the classical literature of chamber music. I

grew up with the sound of string quartets in the living room. My mother had a
similar background, and she too was proficient in languages and music. My
elder brother, who later became Professor of Biology and Master of Dunster
House at Harvard, already p layed the violin well at the time
the cello in

was started on

1922. On several occasions my scientific career has been in

fluenced indirectly, but importantly, by music.

0066-4278/87/0315-0001$02.00

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PAPPENHEIMER

My father loved his work, and the excitement of his research permeated our
family life. Students and colleagues from many parts of the world came to
visit, and as far back as I can remember our conversations at home included
science. Sometimes I was taken to the lab to share the excitement firsthand
and listen to scientific palaver over a sandwich lunch with my father's
colleagues. Much of the vocabulary of biology was mine by the time I was
twelve years old, and about this time, my father began taking me to meetings,
including Harvey Lectures at the Academy and evening joint sessions of
FASEB when they were in New York. We went to these lectures in the same
spirit as we went to concerts. My father often complained ruefully that he did
not know enough chemistry and physics to solve his research problems, and
perhaps it was for this reason that I inclined towards physiology, which
depends so heavily on the exact sciences.
On sabbatical years my father travelled extensively in Europe, Russia, and
the Far East. I began my schooling at the Ecole Alsacienne in Paris in 1921.
Classes were from 8:30 to 4:30 with daily homework as well. The pace was
faster than in America, and on returning home I skipped one and one-half
grades at our local elementary school in Scarsdale. Later I was sent to the
Lincoln School in New York City, one of the leading progressive schools of
its period. I entered Harvard at 16, intellectually prepared but too young to
enjoy fully the broad educational and social opportunities Harvard had to
offer. My father was a devoted Harvard man, and it did not occur to any of his
children to apply elsewhere. It was 1932 and we, the freshmen, were observ
ers of the Great Depression, but few of us were a part of it. Harvard had yet to
reach out for the best and brightest, and we took for granted a Certificate of
Admission and full financial support from our parents. To paraphrase T. S.
Eliot (3):
We came this way, taking the route we were
most

likely to take

From the place we would most likely come from ...

Either we had no purpose or the purpuse was
beyond the end we had figured and was

altered in fulfillment.

I concentrated heavily in science but did not do particularly well in formal

courses and in the end failed to obtain honors. My tutor was Jeffries Wyman,
Jr., who introduced me to quantitative biology in general and to the physical
chemistry of proteins and amino acids in particular. In the parlance of the
1980s, Wyman would be considered a molecular biologist, and indeed, his
contributions to the mechanism of the Bohr effect and the general theory of
allosteric reactions of proteins are cornerstones in modem theory of protein
function (27). I was in awe of his command of thermodynamics and mathe
matics, Our j oint work on the surface tension of solutions of dipolar ions was

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A SILVER SPOON

published in the Journal of the American Chemical Society (23) in 1936.

Jeffries (though of course I did not then address him so) wrote the first draft
and gave it to me for criticism. I rewrote some of it, added a whole new
section, and handed back the manuscript in fear and trepidation. He studied
the changes and without hesitation or emotion said, "It is much improved, but
now you must be the senior author." Not long ago I was flattered on two
counts when a well-known biophysicist in England asked me whether my
father had written this enduring paper.
In the summer of 1935 I took the Physiology course at Woods Hole under
the direction of Laurence Irving. Our instructors included such distinguished
biophysical chemists as Leonor Michaelis and Rudolf Haber; the latter taught
me how to prefuse frog kidneys via the portal system and how to cannulate a
frog's ureter. Later, the 1945 edition of Hober's Physical Chemistry of Cells
and Tissues became one of the most well-worn books in my scientific library.
At the end of the course, I was awarded the Collecting Net Prize ($50 was a
lot in those days) to come back the next summer to work on the kinetics of
CO2 transport and carbamino formation in fish blood with J. K. W. Ferguson,
who had just published important work with Roughton on carbamino hemo
globin in human blood. We did not find carbamino hemoglobin in fish bood,
but we did find an anomalous distribution of HC03 and Cl- in elasmobranch
red cells and duly published in the Biological Bulletin (5).

ROOTS IN ENGLAND
In the autumn of 1936 I sailed for England with a letter of introduction to Sir
Joseph Barcroft from Jeffries Wyman. An aunt had left me a legacy of about
$2000 a year, and this was more than sufficient to support a research student
in pre-war England. What would I have done without it? I arrived in Cam
bridge not yet 21 but eager to begin work in the laboratory. I learned,
however, that Sir Joseph was in the United States and would not return until
October. I spent the next few weeks practicing the cello and reading old Norse
poetry in the University library. When Sir Joseph returned, he was extremely
kind to me, perhaps because he was fond of my brother-in-law, Will Forbes,
who had worked with him ten years previously. He gave me a small research
project on fetal red cells and arranged for me to take the Part II honors course
in Physiology, an experience for which I am endlessly grateful. I was
dreadfully self-conscious, and I admired Sir Joseph so much that I could
scarcely speak in his presence. He seemed to sense this and made a point of
sitting next to me at laboratory teas and trying to put me at ease by telling
funny stories and anecdotes. There were eight Part II students, selected from
some 300 who had taken Part I. Our instructors included E. D. Adrian, B. H.
C. Matthews, F. R. Winton, E. B. Verney, W. A. H. Rushton, and F. J. W.

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PAPPENHEIMER

Roughton, and I developed life-long aSSOCiatIOns with all of them. Alan

Hodgkin was a teaching assistant in the practical class; his job was to come in
early in the morning to decerebrate cats for our class experiments. There were
five lectures a week for three full terms, and each lecture involved analysis of
significant papers in the field. We came to know the important literature in
almost every aspect of physiology and in three languages. During the spring
term I was introduced to F. R. Winton's experiments on isolated perfused
mammalian kidneys, and this opened the door to a new world for me.
Winton was then Reader in Physiology at Cambridge and the author, with
L. E. Bayliss, of a widely used elementary textbook of physiology. He had
trained at University College, London, under Starling, W. M. Bayliss, Ver
ney, Lovatt Evans, and A. V. Hill. Sir William Bayliss's "Principles of
General Physiology" represented for me (and still does) the essence of all that
is good in physiology, but I thought of Bayliss as someone who had lived long
ago. It was amazing and thrilling for me to talk with someone who had been a
close friend of both Starling and Bayliss. In Winton's hands the original
Starling-Verney heart-lung preparation developed into a sophisticated tech
nique for perfusing isolated organs from a pump-lung circulation; it was the
forerunner of modem artificial heart and life-support systems. I was spell
bound by the sight of an isolated dog kidney sitting on a glass plate and
producing clear golden urine from thick red blood.
Winton was an expert with instrumentation, and he designed most of his
own transducers, amplifiers, recording oscillographs, etc. The perfusion
apparatus was itself a complex, inorganic organism-a maze of motors,
plumbing, and electrical devices for measuring, recording, and controlling
flows, pressures, temperatures, ion concentrations, and blood oxygen satura
tion. All of this appealed enormously to my scientific senses; it seemed to me
to be the ideal compromise between in vitro research and the unsatisfying
complexities of whole animal research. I was swayed, also, by the fact that
Winton was a fine cellist and his wife, Bessie Rawlins, was one of the
foremost concert violinists in England. They invited me home to play second
cello in the great Schubert C major quintet (Opus 163), and this settled
matters for me. I had been brought up with the Schubert but never had I
played it with such accomplished musicians. Winton, together with Grace
Eggleton (later to become Mrs. Leonard Bayliss), was about to start an
investigation of renal oxygen consumption as a function of osmotic work of
urine formation. He welcomed me as a graduate student, possibly because of
my previous training in physical chemistry and blood-gas transport; or was it
because of my interest in string quartets? Two foreign postdoctoral fellows
were working with Winton at this time: Jim Shannon (later Director of NIH)
was there to compare inulin with creatinine clearances in the isolated kidney,
and Kurt Kramer from Gottingen was there to develop, with Winton and

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A SILVER SPOON

Glenn Millikan, a spectrophotometric device for continuous recording of

arteriovenous oxygen differences in flowing blood. It must be remembered
that in 1936 solid-state photocells were in their infancy, and the success of
this project depended on the spectral characteristics of a prototype selenium
barrier cell made only in Germany. Five years later Kurt Kramer in Germany
and Glenn Millikan and I in the United States used this experience to develop
the ear oximeter (15). In the meantime, Winton, Eggleton, and I produced a
series of papers on the mechanisms of urine formation in perfused kidneys. It
was the start of a close personal relationship, which lasted until Frank
Winton's death in 1985. Winton's ingenious techniques for estimating renal
glomerular pressure (2, 26) provided the basis for my own first contributions
to capillary physiology a decade later.
In this period, also, I came to enjoy student life in Cambridge. I played in
the University Orchestra and took part in activities at Clare College. On a
dark, cold winter's night we (the University Orchestra with soloists from
London) performed Verdi's Requiem in King's Chapel, the most beautiful
setting imaginable for this gorgeous music. William and Marjorie Rushton
also played in the orchestra, and through them, I was invited to Music Camp
in the Berkshire Downs. This, too, opened the way for life-long friendships. I
was an avid skier and spent memorable winter holidays in the Alps and in the
rugged lotunheimen of central Norway. At Finse I raced in the downhill
(Class C), coming in 89th in a field of 115 entrants. I was the only foreigner,
as was duly noted by the Oslo and Bergen newspapers.
In 1938 Winton moved to the Chair of Pharmacology at University Col
lege, and he took me with him as research student on leave from Cambridge.
Hermann Rein, one of the most prominent physiologists in Germany (and
Kurt Kramer's chief), had just published a paper alleging that metabolism of
resting muscle -was regulated by the sympathetic nervous system. Winton
suggested that I look into this in perfused hindlimb preparations, utilizing the
methods for recording blood oxygen we had used for studies of renal metabo
lism. I was able to confirm Rein's surprising results, but I found a much
simpler explanation for them that was based on sympathetic control of the
microcirculation rather than on metabolism (17). This project gave me experi
ence with the perfused hindlimb preparation, which I eventually used for
studies of capillary permeability.
Of course we worked under the constant threat of war and with nagging
inner voices telling us to stop everything worthwhile to prepare for it.

WAR YEARS
War came on September 2, 1939. I was on vacation at a music houseparty in
Harvard, Massachusetts, and I intended to return to University College as

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PAPPENHEIMER

Demonstrator in Pharmacology. Passports were cancelled, along with my job.

Winton became Dean of the Medical School, which was removed to Surrey
before its buildings were destroyed during the Blitz of 1940. I sought help
from A. N. Richards at the University of Pennsylvania. When I came for an
interview, I launched into a detailed account of my work on perfused muscle,
but he soon interrupted. "All I want to know," he said, "is whether you are a
good experimenter." Tom between outward modesty and inner faith, I finally
opted for the latter, and that was the end of the interview. He set me up with a
temporary appointment in Bazett's Department of Physiology and an
emergency research grant of $250, which enabled me to complete work begun
in England and to send in two papers to the Journal of Physiology. At the
same time, I joined forces with Glenn Millikan to help develop the ear
oximeter. Glenn, like myself, had been cast adrift from his position in
England, and he sought help from Detlev Bronk at the Johnson Foundation for
Medical Physics. It seemed obvious that the US would soon be in the war, and
all of us wanted to contribute what we could as scientists as soon as possible.
For the next six years, Glenn and I worked closely together on oximetry, on
oxygen demand valves, chemical oxygen generators, carbon monoxide
poisoning in tanks and military aircraft, positive pressure breathing, and other
problems in applied physiology for the military.
Let me digress for a moment to pay tribute to Glenn Millikan, who was
killed in a mountain climbing accident in 1947. He was the son of Robert A.
Millikan, President of the California Institute of Technology, who was fa
mous for the oil drop experiment used to measure the charge of the electron.
Glenn was known as "the little oil drop." He was probably the most well
known and charismatic young physiologist of his day in Europe and America.
He exuded energy, curiosity, and joie de vivre. He found his way from
Harvard to Cambridge, England, where he did highly original and important
work on myoglobin, which culminated in a Physiological Review in 1939
(14). He was elected to a Fellowship at Trinity College, where he became a
source of inspiration to students of physiology. He is still remembered with
affection by colleagues in both Europe and America, and certainly his pre
mature death deprived American physiology of one of its most promising
young scientists.
In 1939, our Air Force was woefully lacking in equipment for high-altitude
flying, and only a few physiologists had the knowledge and the vision to
understand what was needed. Among these few were Bruce Dill, Detlev
Bronk, and Walter Boothby. The Aeromedical Research Laboratory at Wright
Field consisted of one altitude chamber and two or three poorly equipped
laboratories staffed by a few junior medical officers and enlisted men. There
was no formal provision or support for civilian research in this area, and
during 1940 Glenn and I usually made the long trip out to Dayton in our own

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A SILVER SPOON

car. Operational aircraft seldom flew above 18,000 feet, and in most cases
they were equipped with rudimentary oxygen equipment. Only three years
later, the USAF sent more than 10,000 fighting men aloft daily in un
pressurized aircraft to operate for many hours at altitudes where conscious
ness would fail within a few seconds without supplementary oxygen. The
enterprise as a whole required vast training programs in the use of oxygen, as
well as continual work to improve the design and efficiency of oxygen
equipment, which competed in weight with the load of gasoline and arma
ment.
Bronk saw the magnitude of these problems at an early stage, and he
became a leader for both the military and civilian effort. Most of the time he
worked directly out of the Air Surgeon's office in Washington, but he retained
a small group at the Johnson Foundation to carry out applied research on
oxygen equipment and on visual problems. Those of us who worked in his
home laboratory as civilians had continual access to operational problems and
to the flight testing facilities of the services and the aircraft industry. We spent
hundreds of unhealthy hypoxic hours testing experimental equipment at sim
ulated altitudes of 40,000 feet or more and temperatures of -400 in the
altitude chamber in Philadelphia.
I also participated in experimental flights to extreme altitudes in stripped
down B-17s and in the first prototype B-29 heavy bomber just prior to its
disastrous loss with all hands aboard in December 1942. I did a survey of
carbon monoxide from gunfire in tanks and aircraft, and the Navy asked me to
test a chemical oxygen generator retrieved from a Japanese Zero shot down in
the Pacific. I found 0.1 % CO in the oxygen. The Navy broadcast this result to
the Japanese, hoping it might shake the confidence of their pilots in their
equipment; at the same time, my report was classified as secret in the US, so I
could no longer read it or keep it in my files.
Most of the time, at least up to 1944, we worked long hours and with a
sense of urgency. Bronk was tireless; he would often arrive from Washington
late in the day, talk with us until midnight and then return to Washington. I,
too, led a somewhat frenetic and heady life of travel to military establishments
and aircraft factories all over the country, not to mention frequent trips to
Washington. Nevertheless, I remained in touch with a saner world through
playing in string quartets, mostly with Catherine Drinker Bowen and with
Helen Rice, who later founded the Association of Amateur Chamber Music
Players, an international organization which now has more than 6000 mem
bers.
I had been brought up in an academic world that emphasized distinctions
between "pure" and "applied" science. 1 was surprised and excited by the
rapidity with which knowledge, previously considered interesting but useless,
could be transformed to practical use on a large scale. Conversely, exposure

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PAPPENHEIMER

to practical problems often stimulated new questions in the realm of fun

damental science. Certainly, this was true of respiratory physiology, which
advanced rapidly in fundamental ways under the stimulus of applied research
for the military. This was a lesson for my generation of academic scientists, a
lesson which in its broader context was transformed into public policy after
the War.
My own experience with applied research during the War was immensely
enriched by close association with Detlev Bronk and the small group of
biophysicists in his entourage, including Keffer Hartline, Frank Brink, Martin
Larrabee, John Hervey, Glenn Millikan, and John Lilly. They were all
experts in instrumentation, especially electronics. We were a close-knit fami
ly, and one would have to be very impermeable indeed not to learn by osmosis
from daily association with such alert and knowledgeable minds.
By 1945, however, the War's end was in sight and all of us were "de
exhilarated" and eager to return to academic life. The project I was then
working on, the storage of oxygen in the form of perchlorates, was already in
pilot production in Pittsburgh, but it seemed unlikely to me that it would ever
be used for its intended purpose as a source of emergency oxygen for aircraft
or for portable welding apparatus. I was anxious to resume studies of the
microcirculation, and after V-J Day it was natural for me to apply to E. M.
Landis, an authority on capillary circulation who had just succeeded W. B.
Cannon as the Higginson Professor of Physiology at Harvard. He had not yet
made new appointments of faculty rank, and I had the good fortune to be
selected as his right-hand man.
CAPILLARIES AND MEMBRANE PERMEABILITY

(1946-1954)
I arrived in Boston in December 1945 to start a new life. There was a heavy
load of teaching awaiting me. Gene Landis had organized a super course in
mammalian physiology; all chapters of the fat textbooks of physiology were
represented in both lecture and lab. It was a veritable dinosaur of a course,
doomed to extinction as new branches of biology evolved to dominate the
medical curriculum. For me it meant another period of intensive work and
learning; I was frequently on deck at 6 AM to prepare live demonstrations or
student labs prior to my 9 AM lecture.
It was not until June 1946 that I found time to resume experimental work. I
had a vague plan for studying edema formation in isolated perfused muscle
but without any clearly defined goal. NIH had not yet started large-scale
support for university-based medical research, but even if it had, I don't think
I could have written an acceptable request for a grant. Certainly I had no
inkling that the project would lead rather swiftly to a logical sequence of

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A SILVER SPOON

enduring advances in the physiology of the microcirculation and the biophys

ics of membrane transport. After only a few experiments, I saw how to set the
mean capillary pressure to known values, how to measure the effective
osmotic pressure exerted by the plasma proteins across capillary walls, and
how to relate these to rates of net filtration and absorption. In the following
year, these preliminary experiments were verified and extended in detail with
Armando Soto-Rivera; they were first presented at the 17th International
Congress of Physiology held in Oxford in 1947. It was the first Congress after
the War, and physiologists were happily reunited after many years of forced
separation. It was a moving contrast to the grim Congress in Zurich which I
had attended in 1938, just prior to the invasion of Czechoslovakia. August
Krogh listened to my paper at Oxford; afterwards he came "backstage" to say
nice things about it, and of course I was thrilled because his work in
respiratory, comparative, and capillary physiology was (and still is) such a
large part of our heritage. At the closing plenary session in the beautiful
Sheldonian Theatre, Albert Szent-Gyorgi gave a speech of thanks in nine
different languages.
The methods developed for measurement of capillary pressure and effective
transcapillary protein osmotic pressure were soon extended to the analysis
of transcapillary concentration gradients during diffusional exchange of
hydrophilic solutes between blood and tissues. This, in tum, led to a general
theoretical analysis of the relations between restricted diffusion, hydrodynam
ic flow, and molecular sieving-an analysis applicable to a wide variety of
biological and artificial membranes. The theory and preliminary results were
first presented (with E. M. Renkin and L. Borrero) at the 18th International
Congress of Physiology in Copenhagen in 1950, under the title Filtration and
Molecular Diffusion
cerning the Number and Dimensions of Ultramicroscopic Openings in the
Capillary Wall. The complete paper subsequently appeared in the American
Journal of Physiology (25). I recently wrote a history of this development and
its relation to the parallel development of irreversible thermodynamics as
applied to membrane transport (21). The American Physiological Society
Handbook volumes on Microcirculation (edited by E. M. Renkin and C. C.
Michel) provide full review of the many modifications and extensions of the
original theory that have been made in the last 35 years.
In 1949 I married Hylie Palmer, a violinist at the lulliard School of Music
and a pupil of Galamian. She has been first fiddle in my life ever since.
Alexander Forbes was still in the Department of Physiology at Harvard
when I arrived in 1946, and it was a great privilege to come to know him. He
was a pioneer in electrophysiology and one of its most distinguished leaders
for more than 50 years (13). He was the first to use vacuum tube amplifiers in
conjunction with the string galvanometer for recording nerve action potentials

10

PAPPENHEIMER

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(6), which set the stage for the classic work of Gasser and Erlanger on
p eripheral nerve and of Adrian, Bronk, Zotterman, Matthews, and others on
single unit analysis in sensory systems (8). Alex was also a pioneer of oblique
photogammetry from the air and an authority on off-shore navigation. In 1935
he mapped northern Laborador and Baffin Land from his own plane, thus
charting the way for the northern air route to Europe during World War 11(7).
He was awarded the Charles Daly Medal of the Geographical S ociety , and his

election to the National Academy of Sciences might equally well have been
for his contributions to geographical science as to neurophysiology. H e
seemed to know every inch of the New England coast and how it had changed
during the sixty years he sailed it. He was a marvelous raconteur. In the
evening after a long day s sail, he would relax over a "Chickatawbut"
cocktail in the cabin of his ketch Stormsvala and draw on an endless repertoire
,

'

of stories and anecdotes, which he always introduced by saying who had told
it to him and when. There must have been dozens of young people, including
my wife and me, who thought of him affectionately as Uncle Alex.
During the 1950s the American Heart Association established some fel
lowships designed to relieve young professors from administrative duties, and
I was selected for one of these generous lifetime awards. This allowed me to

continue laboratory work on a small scale in company with occasional

graduate students and postdoctoral fellows. It also gave me the freedom to
explore novel ideas without worrying about short-term success or failure. My
first effort was indeed a failure. I had the idea that several puzzling features of
the renal circulation might be explained by plasma skimming in the in
terlobular arteries and afferent arterioles. This idea turned out to be incorrect,
at least in the renal cortex. Although my theory, which was presented as a
Bowditch Lecture and elsewhere (22), failed to survive, it nevertheless
stimulated live ly discussion and experimentation for several years and I do not
regret being wrong in this case
.

GOATS

Beginning in 1957 I undertook development of techniques for perfusion of the

ventricular system in unanesthetized animals. I was stimulated by the work of
I. Leusen from Ghent, who had shown that perfusion of the ventricles with
acid solutions caused hyperventilation in anesthetized animals even though
the arterial blood became alkaline (11). Previous theories of chemical regula
tion of breathing were concerned solely with the composition of blood, and it
seemed to me that Leusen's experiments had some exceptionally important
implications for this field. No one had ever perfused the brain ventricular
system in unanesthetized animals, and I had no experience with sur gery for

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A SILVER SPOON

11

chronic experiments. My friends in the Neurosurgery Department were very

skeptical about the feasibility of chronic cannulation of the cisterna magna.
We found, however, that the size and shape of the skull in goats or sheep
make possible the implantation of guide tubes through thick occipital bone
pointing towards the atlanto-occipital membrane. The cistern could then be
punctured at will through the guide tube without causing pain to the un
anesthetized animals. At the same time, Feldberg, in England, described
techniques for chronic implantation of cannulae in cerebral ventricles (4); so
the stage was set for ventriculo-cisternal perfusions in goats. Nevertheless, it
took us almost five years to perfect the surgical techniques and to learn how to
carry out perfusions of the brain for long periods in healthy, confident
animals. Eventually, the project was productive in three disparate fields of
physiology, as follows:
l.Exchange of materials between blood and cerebrospinal fluid (CSF), in
cluding the first measurements of CSF production and absorption by clear
ance techniques. The results were first presented in 1961 at the International
Congress of Pharmacology in Stockholm and have since been described in
reviews and textbooks.
2.Central chemical control of breathing [reviewed in a Harvey Lecture, 1967
(18)] .
3.1nvestigation of sleep-inducing factors released into CSF during sleep
deprivation [reviewed for Scientific American, 1976 (19) and in a Bayliss
Starling Lecture, 1982 (20)].
It would be difficult to initiate a project of this kind at a reputable medical
school of the 1980s. My assistant, Jim Nicholl, never went to college, but he
was a jack-of-all-trades who could do everything from metal spinning in the
machine shop to milking goats. In fact, he became more adept than I at
implanting cisternal guide tubes. Together we built a goat shed and fences
amid the ventilators on the roof of the Medical School, and we did not even
ask permission from Buildings and Grounds. We found farmers (within a
radius of 100 miles) who would supply us with their "surplus" goats free of
charge. We transported goats and hay in my station wagon. In summer the
operated animals (with neckbands to protect their carotid loops and aluminum
hats attached to their horns to protect ventricular guide tubes) travelled with us
for vacations at our summer home in the Berkshires. Astonishment, laughter,
and curiosity were plain to see in the faces of motorists who passed our station
wagon with its cargo of capped goats and children. At about this time I began
to serve on national committees in Washington and elsewhere, and the
airplanes often passed over the Medical School, where I could look down to
see my goats capering on the roof.

12

PAPPENHEIMER

All of this would be illegal today, and the cost of purchase and care of more
than a hundred goats in accredited facilities would be quite out of line with the
potential of the project as it was viewed at the time.

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SLEEP
It was my habit to spend Saturday mornings browsing amongst the journals of
the week. That was how I stumbled on an article by Monnier and Hosli with
the intriguing title Humoral transmission of sleep and wakefulness; hemo
dialysis of a sleep-inducing humor during stimulation of the thalamic
somnogenic area (16). That article referred me to Pieron's early work on the
sleep-inducing properties of CSF drawn from sleep-deprived animals. A copy
of Pieron's 1913 monograph Le probleme physiologique du sommeil was at
hand in our departmental library. On several occasions I have been to the
library to browse or to look up a specific reference and was led by chance to
an unrelated paper that changed the course of my subsequent research. This
sort of serendipity is something the computer cannot supply and I am re
minded again of the quotation from T. S. Eliot's Four Quartets paraphrased
in the prelude to this essay. In this case I realized at once that my colony of
goats provided the means for collecting large quantities of CSF from sleep
deprived animals, and I resolved to "give it a fling." Jim Nicholl and I rigged
up a system to keep the goats awake while Tracy Miller and Cecilie Goodrich
implanted ventricular cannulae in cats to enable us to introduce CSF from the
goat into the cats. To our surprise, the very first experiments corroborated
the findings of Pieron: CSF from a sleep-deprived goat infused into the
ventricles of a cat appeared to make the cat torporous for several hours,
whereas normal fluid from the same goat had no effect. Of course we had no
EEG to judge the nature of the induced sleep, but we all agreed about the
behavioral effects in the three cats tested.
Our first publication in this field was in 1967 (24), and it was followed by
15 years of frustrating attempts to isolate and identify "the" sleep factor. Early
in the project I was joined by Manfred Karnovsky, a distinguished biochemist
who was (and still is) sympathetic to old-fashioned physiology and physiolo
gists. Our starting material changed from CSF derived from sleep-deprived
goats (six liters obtained laboriously from 25 goats over a three-year period),
to the brains of 15,000 sleep-deprived rabbits, to 5000 liters of normal human
urine. We had many collaborators, but much of the credit for the final
isolation and identification of an active muramyl tetrapeptide from urine
belongs to Dr. James Krueger ( 10, 12). The natural product and certain
synthetic muramyl peptides have now been shown to induce high-amplitude,
slow-wave sleep in rats, rabbits, cats, and squirrel monkeys. I am still not

A SILVER SPOON

13

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convinced, however, that the material isolated from urine is related to the
sleep-inducing Factor S we originally found in the CSF of sleep-deprived
animals. The latter is surely of importance to normal physiology, but there are
reasons to believe that the muramyl peptides are involved in immunological
reactions to bacterial infection, including fever as well as sleep. The history of
this still controversial subject has been reviewed in several recent publications
(1, 9, 10, 19, 20).

INTERNATIONAL

The romance of travel to international meetings has been badly tarnished by

the j e t. The up and coming young physiologist thinks nothing of waltzing off
to Europe for three-day meetings several times a year, attache case and 2 x 2
slides in hand. There is prestige value when the secretary can answer phone
calls with "Dr. S. is out of the country until Thursday. Do you want him to
call?" The airport at landing is the same as the one at take-off, and Hilton
Budapest is not much different from Hilton-San Diego or New Delhi.
It was not always so. Less than 40 years ago the triennial International
Congresses of Physiology were about the only international meetings for
biochemists, endocrinologists, nutritionists, and pharmacologists, as well as
physiologists; and there was no such word as neuroscience. Biological scien
tists, young and old, saved their pennies for the triennial treat. It was
unethical to use research funds for travel to meetings, even to local FASEB
meetings. It took a week to cross the Atlantic (depending on the weather), and
it did not make sense to embark on such a long trip without spending at least a
month on the other side. How to compare the excitement of a midnight
sailing, the sound of the bugle warning visitors off the ship, the rattle of
chains as the gangplank is raised and the hawsers cast away, cutting one loose
from home with no way of quick return even in emergency-how to compare
this, I say, with the long line of tired, vetted passengers boarding Flight 6339,
which might just as well be going to Kansas City as to Paris or Copenhagen?
The scientists I admired most, both in England and America, were in
ternationally minded, and my generation of physiologists inherited a strong
tradition of loyalty to THE International Congress of Physiology. I attended
most of these Congresses from 1938 onwards. In 1964, when Wallace Fenn
asked me to be Program Director for the 1968 Congress in Washington, D.C.,
I jumped at the chance. From then until 1983 I had the joy and privilege of
working with Councils of the lUPS together with my counterparts from the
USSR, Poland, Hungary, South America, India, Australia, and Japan, as well
as those from Western Europe and Scandinavia whom I already knew well.
One of my main concerns in this period was to maintain strong representation
-

14

PAPPENHEIMER

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of "Neuroscience" within !UPS, in hopes that this most exciting part of

physiology would not break away into a separate union. It seems to me that
physiology in the United States has suffered greatly by the establishment of
separate departments or divisions of neuroscience within universities, national
societies, and academies. This has not occurred in other countries, where
departments and societies have moved with the times to incorporate the
enlarged scope of modem neurophysiology in which immunology, peptide
chemistry, embryology, etc play such important roles. It may be that the size
and success of developments in neuroscience within the United States made
fission inevitable, but whatever the reason, it has adversely affected many
departments of physiology across the land.
In addition to service with IUPS, I have had many other opportunities to
participate in international meetings or projects, some in exotic places. In
1957, after a lecture tour of Swedish universities, I revisited 10tunheimen on
skis to replay the adventures of 20 years previously. Bjorn Folkow from
G6teborg accompanied me on this expedition, during which we skied to
Storbreen glacier. There my oid friend Per Scholander was extracting gas
bubbles from the ice to estimate the composition of the atmosphere at the time
the glacier ice was laid down. In 1942 Scholander and I almost lost our lives
when we were caught for three days in a severe blizzard on the summit of Mt.
Mansfield in sub-zero temperatures and high wiI}ds. Other memorable ex
peditions, all in the name of Physiology, were in Kashmir, in the foothills of
the Himalayas; in the alps of Southern New Zealand; and in Valdivia, 1 6
hours b y train south o f Santiago, Chile.
On two occasions I returned to England for full years; first as Overseas
Fellow of Churchill College, Cambridge, and subsequently as Eastman Pro
fessor and Supernumerary Fellow of Balliol College, Oxford. These were
years for renewal of old friendships, cementing of new ones, and the sharing
of both with my wife and children. Three of our children continued for five
years or more in England to complete their schooling and university educa
tions. All of them chose art, music, or literature as a life work: not an easy
way to earn a living, and I admire their courage and idealism. It seems
unlikely that the Arts will ever receive even a small fraction of the support
given to Science in the second half of the 20th century.
ACKNOWLEDGMENTS

Parts of this essay will also appear in Men and Ideas in Membrane Transport,
an American Physiological Society Centennial volume (21). I thank the
editors for their permission to use some of the same wording in each of these
two publications.

A SILVER SPOON

15

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Literature Cited
1. Borbely, A., Tobler, 1. 1980. The
search for an endogenous sle ep
substance'. Trends in Pharmacological
Sciences 1:357-59
2. Eggleton, M. G., Pappenheimer, J. R.,
Winton, F. R. 1940. The relation be
tween ureter, venous and arterial pres
sures in the isolated kidney of the dog. J.
Physiol. 99:135--52
3. Eliot, T. S. 1943. Four Quartets: IV.
Little Gidding. New York: Harcourt
Brace
4. Feldberg, W. 1963. A Pharmacological
Approach to the Brain from its Inner and
Outer Surface. Baltimore: Williams &
Wilkins
5. Ferguson, 1. K. W., Horvath, S. M.,
Pa ppen hei mer, J. R. 1938. The transport
of carbon dioxide by erythrocytes and
plasma in dogfish blood. Bioi. Bull.

75:381-88

6. Forbes,
A.,
T hache r , C.
1920.
Amplification of action currents with the
electron tube in recording with the string
galvanometer. Amer. J. Physiol. 52:
409-71
7. Forbes, A. 1953. Quest for a Northern
Air Route. Cambridge, Mass.: Harvard
Univ. Press
8. Hodgkin, A. L. 1979. Baron Adrian of
Cambridge, Biographical Memoirs of
the Royal Society. London: R. Soc.
9. Inoue, S., Borbely, A . , eds. 1985.
En dog enous Sleep Substances and Sleep
Regulation. Utrecht, The N etherl ands:
VNU
10. Krueger, J. M., Walter, J., Lev in, C.
1985. Endogenous sleep factors. In
Brain Mechanisms of Sleep. ed. D.
McGinty, pp. 253-75. New York:
Raven
II. Leusen, I. R. 1954. Chemosensitivity of
the respiratory center. Influence of CO2
in the cerebral ventricles on respiration.
Amer. J. Physiol. 176:39-44
12. Martin, S. , Kamovsky, M. L., Kruegcr,
J. M. , Pappenheimer, J. R. , Bieman, K.
1984. Peptidoglycans as promoters of
slow wave sleep; structure of the sleep
p ro mo ting factor isolated from human
urine. J. Bioi. Chern. 259:12652-58
13. Memorial minute on the life of Alexan
der Forbes. Harvard University Gazette
LXI. No . 5 1965.
14. Millikan, G. A. 1939. Muscle hemoglo
bin. Physiol. Rev. 19:503-23

15. Millikan, G. A., Pappenheimer, J. R. ,

Rawson, A. J., H erv ey, J. P. 1941. The
continuous measurement of arterial sat
uration in man. Amer. J. Physiol.
133:390 (Abstr.)
16. Monnier, A., Hosli, L. 1965. Humoral
transmission of sleep and wakefulness:
II. Hemodialysis of a sleep-inducing
humor during stimulation of the thalamic
hypnogenic area. Pflug. Arch. Ges.
Physiol. 282:60--7 5
17. P appenhe imer, J. R. 1941. Vasocon
strictor nerves and oxygen co nsu mption
in the isolated p erfused hindlimb mus
cles of the dog. J. P hysio l. 99:182-200
18. Pappenheimer, J. R. 1967. The ionic
composition of cerebral extracellular
fluid and its relation to control of breath
ing. Harvey Lecture Ser. 61:71-94.
New York: Academic
19. Pappenheimer, 1. R. 1976. T he sleep
factor. Sci. Amer. 2 3 5 : 24-29
20. Pappenheimer, J. R. 1983. Induction of
sleep by muramyl peptides. (Bayliss
Starling Memorial Lecture) J. Physiol.
336:1-11
21. Pappcnheimer, J. R. Flow and diffusion
through biological membranes. In Men
and Ideas in Membrane Transport, ed.
D. C. Tosteson. Amer. P hy sio l. Soc.
100: In press
22. Pappenheime r , J. R., Kinter, W. B.
1956. Hematocrit r atio of blood within
the mammalian kidney and its signifi
cance for renal hemodynamics. Amer. 1.
Physiol. 185:377-90
23. Pappenheimer, J. R., Lepie, M. P., Wy
man, J. Jr. 1936. The surface tension of
aqueous solutions of dipolar ions. 1.
Amer. Chern. Soc. 58:1851-55
24. Pappenheimer, J. R. , Miller, T. B.,
Goodrich, C. A. 1967. Sleep-promoting
effects of cerebrospinal fluid from sleep
deprived goats. Proc. Natl. Acad. Sci.
USA 58:513-17
25. Pappenheimer, J. R. , Renkin, E. M.,
Borrero, L. M. 1951. Filtration, diffu
sion and molecular sieving through pe
ripheral capillary membranes. Amer. J.
Physiol. 167:13-46
26. Winton, F. R. 1931. The glomerular
pressure in the isolated mammalian kid
ney. J. Physi ol. 72:361-75
27. Wyman, J. Jr. 1964. Linked functions
and reciprocal effects in proteins Adv.
Protein Chern. 19:224-86